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`Remarkable’: CAR T therapy for CLL/SLL
The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.
“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.
Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.
“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.
With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.
In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.
The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 106 CAR-positive viable T cells of liso-cel.
With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).
Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.
The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.
The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).
The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.
The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.
In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.
Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.
Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.
For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.
Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.
One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.
“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.
She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.
“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.
For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”
Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.
“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
Largest data set to date
Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.
“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.
“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”
Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.
Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.
In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”
Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.
“The results of this study are very exciting,” she said during her discussion in the session.
“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”
Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”
The results were also published in The Lancet.
The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.
The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.
“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.
Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.
“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.
With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.
In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.
The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 106 CAR-positive viable T cells of liso-cel.
With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).
Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.
The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.
The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).
The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.
The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.
In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.
Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.
Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.
For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.
Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.
One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.
“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.
She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.
“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.
For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”
Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.
“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
Largest data set to date
Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.
“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.
“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”
Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.
Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.
In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”
Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.
“The results of this study are very exciting,” she said during her discussion in the session.
“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”
Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”
The results were also published in The Lancet.
The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.
The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.
“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.
Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.
“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.
With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.
In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.
The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 106 CAR-positive viable T cells of liso-cel.
With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).
Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.
The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.
The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).
The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.
The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.
In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.
Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.
Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.
For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.
Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.
One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.
“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.
She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.
“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.
For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”
Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.
“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
Largest data set to date
Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.
“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.
“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”
Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.
Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.
In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”
Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.
“The results of this study are very exciting,” she said during her discussion in the session.
“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”
Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”
The results were also published in The Lancet.
The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.
FROM ASCO 2023
FDA approves new indication for avapritinib
Avapritinib, a selective KIT mutation-targeted tyrosine kinase inhibitor, was approved in 2021 to treat advanced systemic mastocytosis, a rare and potentially fatal hematologic disorder. Nonadvanced forms include indolent or smoldering disease; advanced disease can progress to leukemia. The expanded approval now covers patients with indolent disease, which represents the majority of patients with systemic mastocytosis.
The drug is also approved for adults with unresectable or metastatic GIST that harbors a platelet-derived growth factor receptor alpha exon 18 mutation.
The approval is based on data from the phase 2 PIONEER trial. In the trial, 222 patients with moderate to severe indolent, systemic mastocytosis* were randomly assigned in a 2:1 ratio to receive either avapritinib 25 mg once daily plus best supportive care or placebo plus best supportive care.
The findings, published in February, revealed that patients who received avapritinib experienced significantly greater improvements in total symptom scores at 24 weeks (–15.6 vs. –9.2 for control patients). Significantly more patients in the avapritinib arm achieved greater than or equal to 50% reductions in serum tryptase (54% vs. 0%), bone marrow mast cell aggregates (53% vs. 23%), and KIT D816V variant allele fraction (68% vs. 6%).
Most adverse reactions were mild to moderate in severity and included eye edema, dizziness, peripheral edema, and flushing. Fewer than 1% of patients discontinued treatment because of serious adverse reactions.
“People with indolent systemic mastocytosis are significantly impacted by their disease symptoms, and many individuals self-isolate at home to protect against unpredictable external triggers,” Judith Kain Emmel, board chair of the Mast Cell Disease Society, said in the company press release. “Today’s approval is a historic moment for the [systemic mastocytosis] community and offers new hope for patients and their families.
A version of this article first appeared on Medscape.com.
Correction, 5/23/23: An earlier version of this article mischaracterized these patients' conditions. They had moderate to severe indolent, systemic mastocytosis.
Avapritinib, a selective KIT mutation-targeted tyrosine kinase inhibitor, was approved in 2021 to treat advanced systemic mastocytosis, a rare and potentially fatal hematologic disorder. Nonadvanced forms include indolent or smoldering disease; advanced disease can progress to leukemia. The expanded approval now covers patients with indolent disease, which represents the majority of patients with systemic mastocytosis.
The drug is also approved for adults with unresectable or metastatic GIST that harbors a platelet-derived growth factor receptor alpha exon 18 mutation.
The approval is based on data from the phase 2 PIONEER trial. In the trial, 222 patients with moderate to severe indolent, systemic mastocytosis* were randomly assigned in a 2:1 ratio to receive either avapritinib 25 mg once daily plus best supportive care or placebo plus best supportive care.
The findings, published in February, revealed that patients who received avapritinib experienced significantly greater improvements in total symptom scores at 24 weeks (–15.6 vs. –9.2 for control patients). Significantly more patients in the avapritinib arm achieved greater than or equal to 50% reductions in serum tryptase (54% vs. 0%), bone marrow mast cell aggregates (53% vs. 23%), and KIT D816V variant allele fraction (68% vs. 6%).
Most adverse reactions were mild to moderate in severity and included eye edema, dizziness, peripheral edema, and flushing. Fewer than 1% of patients discontinued treatment because of serious adverse reactions.
“People with indolent systemic mastocytosis are significantly impacted by their disease symptoms, and many individuals self-isolate at home to protect against unpredictable external triggers,” Judith Kain Emmel, board chair of the Mast Cell Disease Society, said in the company press release. “Today’s approval is a historic moment for the [systemic mastocytosis] community and offers new hope for patients and their families.
A version of this article first appeared on Medscape.com.
Correction, 5/23/23: An earlier version of this article mischaracterized these patients' conditions. They had moderate to severe indolent, systemic mastocytosis.
Avapritinib, a selective KIT mutation-targeted tyrosine kinase inhibitor, was approved in 2021 to treat advanced systemic mastocytosis, a rare and potentially fatal hematologic disorder. Nonadvanced forms include indolent or smoldering disease; advanced disease can progress to leukemia. The expanded approval now covers patients with indolent disease, which represents the majority of patients with systemic mastocytosis.
The drug is also approved for adults with unresectable or metastatic GIST that harbors a platelet-derived growth factor receptor alpha exon 18 mutation.
The approval is based on data from the phase 2 PIONEER trial. In the trial, 222 patients with moderate to severe indolent, systemic mastocytosis* were randomly assigned in a 2:1 ratio to receive either avapritinib 25 mg once daily plus best supportive care or placebo plus best supportive care.
The findings, published in February, revealed that patients who received avapritinib experienced significantly greater improvements in total symptom scores at 24 weeks (–15.6 vs. –9.2 for control patients). Significantly more patients in the avapritinib arm achieved greater than or equal to 50% reductions in serum tryptase (54% vs. 0%), bone marrow mast cell aggregates (53% vs. 23%), and KIT D816V variant allele fraction (68% vs. 6%).
Most adverse reactions were mild to moderate in severity and included eye edema, dizziness, peripheral edema, and flushing. Fewer than 1% of patients discontinued treatment because of serious adverse reactions.
“People with indolent systemic mastocytosis are significantly impacted by their disease symptoms, and many individuals self-isolate at home to protect against unpredictable external triggers,” Judith Kain Emmel, board chair of the Mast Cell Disease Society, said in the company press release. “Today’s approval is a historic moment for the [systemic mastocytosis] community and offers new hope for patients and their families.
A version of this article first appeared on Medscape.com.
Correction, 5/23/23: An earlier version of this article mischaracterized these patients' conditions. They had moderate to severe indolent, systemic mastocytosis.
FDA OKs stem cell therapy for blood cancer patients to reduce infection risks
Omidubicel is made from umbilical cord donor stem cells that are processed with nicotinamide, a form of vitamin B3, to enhance and expand the number of progenitor cells, the product’s maker, Jerusalem-based Gamida Cell, explained in a press announcement.
The FDA approval was based on phase 3 testing that pitted the use of omidubicel in 62 patients against standard unmanipulated cord blood transplants in 63 patients following myeloablative conditioning.
The median time to neutrophil recovery was 12 days in the omidubicel group, compared with 22 days with standard care. Overall, 87% of patients who received omidubicel achieved neutrophil recovery versus 83% of patients with standard transplants.
The incidence of grade 2/3 bacterial or grade 3 fungal infections 100 days following transplant was 39% with omidubicel versus 60% with standard transplants.
The FDA’s “approval is an important advance in cell therapy treatment in patients with blood cancers. Hastening the return of the body’s white blood cells can reduce the possibility of serious or overwhelming infection associated with stem cell transplantation,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in an agency press release.
Abbey Jenkins, president and CEO of Gamida, called the approval “a major advancement in the treatment of patients with hematologic malignancies that we believe may increase access to stem cell transplant and help improve patient outcomes.”
The most common grade 3–5 adverse reactions in the approval study were pain (33%), mucosal inflammation (31%), hypertension (25%), and gastrointestinal toxicity (19%).
Adverse events are consistent with allogeneic hematopoietic stem cell transplantation. Among 117 patients who received omidubicel for any indication, infusion reactions occurred in 47% of patients, acute graft-versus-host disease occurred in 58%, chronic GVHD occurred in 35%, and graft failure occurred in 3%. Labeling includes a boxed warning of the possibilities. There is also a small risk of infections and malignancies from donor blood.
Omidubicel is manufactured in Gamida’s facility in Kiryat Gat, Israel. It is available for order now and is expected to be delivered to transplant centers within 30 days after the start of manufacturing, the company said.
A version of this article originally appeared on Medscape.com.
Omidubicel is made from umbilical cord donor stem cells that are processed with nicotinamide, a form of vitamin B3, to enhance and expand the number of progenitor cells, the product’s maker, Jerusalem-based Gamida Cell, explained in a press announcement.
The FDA approval was based on phase 3 testing that pitted the use of omidubicel in 62 patients against standard unmanipulated cord blood transplants in 63 patients following myeloablative conditioning.
The median time to neutrophil recovery was 12 days in the omidubicel group, compared with 22 days with standard care. Overall, 87% of patients who received omidubicel achieved neutrophil recovery versus 83% of patients with standard transplants.
The incidence of grade 2/3 bacterial or grade 3 fungal infections 100 days following transplant was 39% with omidubicel versus 60% with standard transplants.
The FDA’s “approval is an important advance in cell therapy treatment in patients with blood cancers. Hastening the return of the body’s white blood cells can reduce the possibility of serious or overwhelming infection associated with stem cell transplantation,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in an agency press release.
Abbey Jenkins, president and CEO of Gamida, called the approval “a major advancement in the treatment of patients with hematologic malignancies that we believe may increase access to stem cell transplant and help improve patient outcomes.”
The most common grade 3–5 adverse reactions in the approval study were pain (33%), mucosal inflammation (31%), hypertension (25%), and gastrointestinal toxicity (19%).
Adverse events are consistent with allogeneic hematopoietic stem cell transplantation. Among 117 patients who received omidubicel for any indication, infusion reactions occurred in 47% of patients, acute graft-versus-host disease occurred in 58%, chronic GVHD occurred in 35%, and graft failure occurred in 3%. Labeling includes a boxed warning of the possibilities. There is also a small risk of infections and malignancies from donor blood.
Omidubicel is manufactured in Gamida’s facility in Kiryat Gat, Israel. It is available for order now and is expected to be delivered to transplant centers within 30 days after the start of manufacturing, the company said.
A version of this article originally appeared on Medscape.com.
Omidubicel is made from umbilical cord donor stem cells that are processed with nicotinamide, a form of vitamin B3, to enhance and expand the number of progenitor cells, the product’s maker, Jerusalem-based Gamida Cell, explained in a press announcement.
The FDA approval was based on phase 3 testing that pitted the use of omidubicel in 62 patients against standard unmanipulated cord blood transplants in 63 patients following myeloablative conditioning.
The median time to neutrophil recovery was 12 days in the omidubicel group, compared with 22 days with standard care. Overall, 87% of patients who received omidubicel achieved neutrophil recovery versus 83% of patients with standard transplants.
The incidence of grade 2/3 bacterial or grade 3 fungal infections 100 days following transplant was 39% with omidubicel versus 60% with standard transplants.
The FDA’s “approval is an important advance in cell therapy treatment in patients with blood cancers. Hastening the return of the body’s white blood cells can reduce the possibility of serious or overwhelming infection associated with stem cell transplantation,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in an agency press release.
Abbey Jenkins, president and CEO of Gamida, called the approval “a major advancement in the treatment of patients with hematologic malignancies that we believe may increase access to stem cell transplant and help improve patient outcomes.”
The most common grade 3–5 adverse reactions in the approval study were pain (33%), mucosal inflammation (31%), hypertension (25%), and gastrointestinal toxicity (19%).
Adverse events are consistent with allogeneic hematopoietic stem cell transplantation. Among 117 patients who received omidubicel for any indication, infusion reactions occurred in 47% of patients, acute graft-versus-host disease occurred in 58%, chronic GVHD occurred in 35%, and graft failure occurred in 3%. Labeling includes a boxed warning of the possibilities. There is also a small risk of infections and malignancies from donor blood.
Omidubicel is manufactured in Gamida’s facility in Kiryat Gat, Israel. It is available for order now and is expected to be delivered to transplant centers within 30 days after the start of manufacturing, the company said.
A version of this article originally appeared on Medscape.com.
Venetoclax shows promise for r/r hairy cell leukemia
Venetoclax is already approved for adults with chronic lymphocytic leukemia, small lymphocytic leukemia, and as part of a treatment combination in certain patients with acute myeloid leukemia.
The new findings suggest that the drug could also be a chemotherapy-free treatment option for HCL patients after the failure of multiple prior lines of therapy, including vemurafenib plus rituximab, the investigators wrote in a letter to the editor published in the New England Journal of Medicine.
Treatment options for such patients are limited, they noted.
Enrico Tiacci, MD, of the University of Perugia (Italy), and colleagues decided to explore the use of venetoclax in this patient population after reports of in vitro findings showing a possible benefit.
The investigators administered the drug off-label to six patients who had received vemurafenib plus rituximab as their most recent prior therapy; one was resistant and five relapsed after that therapy, they reported. Venetoclax was delivered in 29-day cycles.
After 6 or 12 cycles, two patients experienced complete remission with minimal residual disease (MRD), and one had partial remission, although each had incomplete platelet recovery.
Adding rituximab at a dose of 375 mg per square meter of body-surface area for three to eight cycles improved the depth of response in a patient who had a previous minor response, further reduced MRD in one who had a complete remission to venetoclax, and led to hematologic remission in one who had no response to venetoclax, they noted.
Progression-free survival ranged from 23 to 53-plus months in all five patients who did not have early progression and was similar or better than PFS seen after vemurafenib plus rituximab.
The main toxic effect of venetoclax was worsening of baseline neutropenia, which was sometimes complicated by infections or febrile neutropenia and was managed by dose reductions and granulocyte colony-stimulating factor.
“Thus, venetoclax with or without rituximab may serve as a safe and effective salvage option after failure of vemurafenib plus rituximab treatment, especially in patients who do not require a rapid recovery of blood count,” they concluded.
The study was supported by grants from Fondazione Associazione Italiana per la Ricerca sul Cancro and the Italian Ministry of Health.
A version of this article first appeared on Medscape.com.
Venetoclax is already approved for adults with chronic lymphocytic leukemia, small lymphocytic leukemia, and as part of a treatment combination in certain patients with acute myeloid leukemia.
The new findings suggest that the drug could also be a chemotherapy-free treatment option for HCL patients after the failure of multiple prior lines of therapy, including vemurafenib plus rituximab, the investigators wrote in a letter to the editor published in the New England Journal of Medicine.
Treatment options for such patients are limited, they noted.
Enrico Tiacci, MD, of the University of Perugia (Italy), and colleagues decided to explore the use of venetoclax in this patient population after reports of in vitro findings showing a possible benefit.
The investigators administered the drug off-label to six patients who had received vemurafenib plus rituximab as their most recent prior therapy; one was resistant and five relapsed after that therapy, they reported. Venetoclax was delivered in 29-day cycles.
After 6 or 12 cycles, two patients experienced complete remission with minimal residual disease (MRD), and one had partial remission, although each had incomplete platelet recovery.
Adding rituximab at a dose of 375 mg per square meter of body-surface area for three to eight cycles improved the depth of response in a patient who had a previous minor response, further reduced MRD in one who had a complete remission to venetoclax, and led to hematologic remission in one who had no response to venetoclax, they noted.
Progression-free survival ranged from 23 to 53-plus months in all five patients who did not have early progression and was similar or better than PFS seen after vemurafenib plus rituximab.
The main toxic effect of venetoclax was worsening of baseline neutropenia, which was sometimes complicated by infections or febrile neutropenia and was managed by dose reductions and granulocyte colony-stimulating factor.
“Thus, venetoclax with or without rituximab may serve as a safe and effective salvage option after failure of vemurafenib plus rituximab treatment, especially in patients who do not require a rapid recovery of blood count,” they concluded.
The study was supported by grants from Fondazione Associazione Italiana per la Ricerca sul Cancro and the Italian Ministry of Health.
A version of this article first appeared on Medscape.com.
Venetoclax is already approved for adults with chronic lymphocytic leukemia, small lymphocytic leukemia, and as part of a treatment combination in certain patients with acute myeloid leukemia.
The new findings suggest that the drug could also be a chemotherapy-free treatment option for HCL patients after the failure of multiple prior lines of therapy, including vemurafenib plus rituximab, the investigators wrote in a letter to the editor published in the New England Journal of Medicine.
Treatment options for such patients are limited, they noted.
Enrico Tiacci, MD, of the University of Perugia (Italy), and colleagues decided to explore the use of venetoclax in this patient population after reports of in vitro findings showing a possible benefit.
The investigators administered the drug off-label to six patients who had received vemurafenib plus rituximab as their most recent prior therapy; one was resistant and five relapsed after that therapy, they reported. Venetoclax was delivered in 29-day cycles.
After 6 or 12 cycles, two patients experienced complete remission with minimal residual disease (MRD), and one had partial remission, although each had incomplete platelet recovery.
Adding rituximab at a dose of 375 mg per square meter of body-surface area for three to eight cycles improved the depth of response in a patient who had a previous minor response, further reduced MRD in one who had a complete remission to venetoclax, and led to hematologic remission in one who had no response to venetoclax, they noted.
Progression-free survival ranged from 23 to 53-plus months in all five patients who did not have early progression and was similar or better than PFS seen after vemurafenib plus rituximab.
The main toxic effect of venetoclax was worsening of baseline neutropenia, which was sometimes complicated by infections or febrile neutropenia and was managed by dose reductions and granulocyte colony-stimulating factor.
“Thus, venetoclax with or without rituximab may serve as a safe and effective salvage option after failure of vemurafenib plus rituximab treatment, especially in patients who do not require a rapid recovery of blood count,” they concluded.
The study was supported by grants from Fondazione Associazione Italiana per la Ricerca sul Cancro and the Italian Ministry of Health.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Inclusive reminder: LGBTQ community may donate stem cells
In fact, gay men have been able to donate stem cells in the United States since 2015. That’s when National Marrow Donor Program’s Be the Match registry lifted restrictions on men who have sex with men (MSM).
Physicians say advocacy is still necessary, because LGBTQ people may assume they can’t donate or be wary of clinicians. “The LGBTQIA+ population in general has experienced a lot of issues with the medical-industrial complex in terms of discrimination and inappropriate care,” said UT Southwestern Medical Center pathologist Brian Adkins, MD, who manages the blood bank at Children’s Health in Dallas, in an interview. “There’s a weariness there that may produce some hesitancy to interact with the donation process.”
An estimated 6.8 million people give blood in the United States each year, and an estimated 9 million people are registered as potential stem cell donors. A total of 22,013 hematopoietic cell transplantation procedures were performed in 2020, according to the U.S. Health Resources and Services Administration.
Expanding the number of LGBTQ donors, especially those born as biological males, could pay major dividends. As Dr. Adkins noted, the ideal stem cell donor is young – Be the Match says doctors generally prefer donors aged 18-35 – and male. According to a 2021 Gallup Poll, 21% of those born from 1997 to 2003 (Generation Z) say they’re LGBTQ, as do 11% of those born from 1981 to 1996 (Millennials).
In North America, the most extensive outreach to the LGBTQ community about stem cell donation has been launched in Canada. There, an organization called Stem Cell Club focuses on encouraging college students and other young people to register as potential stem cell donors.
Stem Cell Club has several campaigns aimed at ethnic minority groups, and its Saving Lives With Pride project focuses on MSM. The project’s web page includes testimonials from a woman whose life was saved by an unrelated gay male donor and from a gay male nurse who recovered from blood cancer thanks to a stem cell donation. The site also includes videos about stem cell donation featuring LGBTQ young people and Canadian hematologists.
“Our specialized collection center will treat donors with the highest levels of respect and courtesy, indeed as heroes of their unselfish gift that can truly save a life,” says Ottawa Hospital transplant hematologist David Allan, MD, in one of the videos.
Stem Cell Club was founded by transplant hematologist Warren Fingrut, MD, a research fellow at Memorial Sloan Kettering Cancer Center. In an interview, he said the organization’s LGBTQ project has promoted stem cell donation at several annual gay pride events and will continue the outreach this coming summer. In 2018 and 2019, advocates recruited 354 potential stem-cell donors (40% male, 42 non-White) at five pride events, Dr. Fingrut and colleagues reported last year in the journal Bone Marrow Transplantation.
For a new study, researchers interviewed 37 gay and bisexual men from five Canadian provinces about stem cell donation. Dr. Fingrut and colleagues reported the findings in February in an abstract at the Transplantation & Cellular Therapy Meetings.
Most participants didn’t know they “are eligible to donate stem cells, with many confusing stem cell versus blood donor eligibility criteria,” the researchers reported. According to Dr. Fingrut, some of the men “felt they were treated as second-class citizens, and that translated into frustration and decreased motivation to donate. There were concerns that they would be treated as though they shouldn’t be there.”
Canada has allowed gay men to donate stem cells for at least 10 years, Dr. Fingrut said. In 2022, Canadian officials said blood banks would no longer require MSM donors to have been abstinent from sex for 3 months, the BBC reported. However, donors will be asked about high-risk sexual behaviors.
The United States, where HIV spread through the blood supply during the early years of the AIDS pandemic and killed thousands of hemophiliacs, has much been slower to change its policies. For decades, starting in the 1980s, both blood banks and stem cell donation programs chose to lower the risk by turning away MSM donors.
Policies only began to change in recent years. Be the Match’s registry led the way by welcoming MSM in 2015. Stem cell donations go through more extensive testing than blood donations, Dr. Adkins said, so it’s more likely that HIV will be screened out. Also, he said, officials probably realized “it was necessary to widen the donor pool in order to best serve the patients” because it’s so hard to find matched stem-cell donors.
Be the Match has also stepped up its outreach to the LGBTQ community. “During Pride Month in 2022, Be The Match sponsored booths at events in 12 major markets from coast to coast,” said Jamie Margolis, senior vice president of Donor Services. “These efforts enabled us to increase awareness among more than 500,000 festival attendees and added more than 2,000 new members to the Be The Match Registry. We also produced a social media awareness campaign featuring one of our own employees, who is a cofounder of the Pride Employee Resource Group at Be The Match and a recent blood stem cell donor.”
In 2020 as blood banks became desperate for donations during the early days of the COVID-19 pandemic, the FDA changed its policy and required MSM to be abstinent for 3 months instead of 1 year before giving blood. (Prior to December 2014, any man who’d had sex with a man, even once, was indefinitely banned from giving blood.)
The 3-month policy instituted in 2020 drew fire from critics such as the American Medical Association, which noted the regulation treated men differently if they had unprotected sex with a single man versus with multiple women.
Now, the FDA is proposing that it once again change the policy about blood donations: It is recommending that there be no special polices regarding MSM. “All prospective donors who report having a new sexual partner or more than one sexual partner and had anal sex in the past 3 months would be deferred from donation.”
Under the proposal, anyone who’s ever had HIV will not be able to donate. (They can’t donate stem cells either.) And the FDA proposes restrictions on those who take pre-exposure prophylaxis or postexposure prophylaxis for HIV.
Margolis, of Be the Match, noted that some members of the LGBTQ community may not be able to donate to Be The Match BioTherapies, which works with cell and gene therapy developers worldwide to provide cellular starting material. “These therapies may have different requirements than those for blood stem-cell transplants. Men who have had sex with men in the past 5 years or women who have had sex with a man who has had sex with a man in the past 5 years may not be able to donate to Be The Match BioTherapies. While we understand this could be upsetting or frustrating for someone who desires to be a part of these therapies, we are committed to following medical guidelines and regulations, while also advocating for our donors and the LBGTQIA+ community as a whole.”
MSM aren’t the only target of outreach by proponents of stem cell donation. In 2019, UT Southwestern’s Dr. Adkins and colleagues wrote a commentary in Bone Marrow Transplantation that called for bone marrow donation centers to do more to be welcoming to transgender donors. “The largest age group identifying as transgender is 18-24 years of life, which overlaps considerably with the population of hematopoietic stem cell donors, which tend to be younger individuals,” the researchers wrote.
The transgender community was “simply overlooked,” Dr. Adkins said. Since then, as he pointed out, things have changed. Now, Be the Match’s website notes that “members of the LGBTQIA+ community CAN join the registry and donate.” The organization says that “for medical reasons, everyone is asked to provide their sex assigned at birth when they register. Should you be called as a match, pronouns and gender identity are respected throughout the process.”
In addition, the site says people on prescription hormone therapy are not excluded from joining the registry. Patients who have undergone surgery within the last 12 months, including sex-reassignment procedures, “will be asked about the current status of their recovery and whether they are still seeing a physician for follow-up in regards to the surgery.”
What’s next? Dr. Fingrut said he expects the lifting of strict rules about MSM and blood donation will boost stem cell donation in the community.
There seems to be plenty of room for more outreach. Cole Williams, founder of Pride & Plasma, which advocates for allowing gay men to give blood, suggested in an interview that advocates who want to increase stem cell donation in the LGBTQ community reach out to its community centers, health organizations, providers, and clinics.
So far, though, “I haven’t seen a big call for registration of any individuals unless they have a personal relation to bone marrow donation,” he said.
Dr. Fingrut and Dr. Adkins report no disclosures.
In fact, gay men have been able to donate stem cells in the United States since 2015. That’s when National Marrow Donor Program’s Be the Match registry lifted restrictions on men who have sex with men (MSM).
Physicians say advocacy is still necessary, because LGBTQ people may assume they can’t donate or be wary of clinicians. “The LGBTQIA+ population in general has experienced a lot of issues with the medical-industrial complex in terms of discrimination and inappropriate care,” said UT Southwestern Medical Center pathologist Brian Adkins, MD, who manages the blood bank at Children’s Health in Dallas, in an interview. “There’s a weariness there that may produce some hesitancy to interact with the donation process.”
An estimated 6.8 million people give blood in the United States each year, and an estimated 9 million people are registered as potential stem cell donors. A total of 22,013 hematopoietic cell transplantation procedures were performed in 2020, according to the U.S. Health Resources and Services Administration.
Expanding the number of LGBTQ donors, especially those born as biological males, could pay major dividends. As Dr. Adkins noted, the ideal stem cell donor is young – Be the Match says doctors generally prefer donors aged 18-35 – and male. According to a 2021 Gallup Poll, 21% of those born from 1997 to 2003 (Generation Z) say they’re LGBTQ, as do 11% of those born from 1981 to 1996 (Millennials).
In North America, the most extensive outreach to the LGBTQ community about stem cell donation has been launched in Canada. There, an organization called Stem Cell Club focuses on encouraging college students and other young people to register as potential stem cell donors.
Stem Cell Club has several campaigns aimed at ethnic minority groups, and its Saving Lives With Pride project focuses on MSM. The project’s web page includes testimonials from a woman whose life was saved by an unrelated gay male donor and from a gay male nurse who recovered from blood cancer thanks to a stem cell donation. The site also includes videos about stem cell donation featuring LGBTQ young people and Canadian hematologists.
“Our specialized collection center will treat donors with the highest levels of respect and courtesy, indeed as heroes of their unselfish gift that can truly save a life,” says Ottawa Hospital transplant hematologist David Allan, MD, in one of the videos.
Stem Cell Club was founded by transplant hematologist Warren Fingrut, MD, a research fellow at Memorial Sloan Kettering Cancer Center. In an interview, he said the organization’s LGBTQ project has promoted stem cell donation at several annual gay pride events and will continue the outreach this coming summer. In 2018 and 2019, advocates recruited 354 potential stem-cell donors (40% male, 42 non-White) at five pride events, Dr. Fingrut and colleagues reported last year in the journal Bone Marrow Transplantation.
For a new study, researchers interviewed 37 gay and bisexual men from five Canadian provinces about stem cell donation. Dr. Fingrut and colleagues reported the findings in February in an abstract at the Transplantation & Cellular Therapy Meetings.
Most participants didn’t know they “are eligible to donate stem cells, with many confusing stem cell versus blood donor eligibility criteria,” the researchers reported. According to Dr. Fingrut, some of the men “felt they were treated as second-class citizens, and that translated into frustration and decreased motivation to donate. There were concerns that they would be treated as though they shouldn’t be there.”
Canada has allowed gay men to donate stem cells for at least 10 years, Dr. Fingrut said. In 2022, Canadian officials said blood banks would no longer require MSM donors to have been abstinent from sex for 3 months, the BBC reported. However, donors will be asked about high-risk sexual behaviors.
The United States, where HIV spread through the blood supply during the early years of the AIDS pandemic and killed thousands of hemophiliacs, has much been slower to change its policies. For decades, starting in the 1980s, both blood banks and stem cell donation programs chose to lower the risk by turning away MSM donors.
Policies only began to change in recent years. Be the Match’s registry led the way by welcoming MSM in 2015. Stem cell donations go through more extensive testing than blood donations, Dr. Adkins said, so it’s more likely that HIV will be screened out. Also, he said, officials probably realized “it was necessary to widen the donor pool in order to best serve the patients” because it’s so hard to find matched stem-cell donors.
Be the Match has also stepped up its outreach to the LGBTQ community. “During Pride Month in 2022, Be The Match sponsored booths at events in 12 major markets from coast to coast,” said Jamie Margolis, senior vice president of Donor Services. “These efforts enabled us to increase awareness among more than 500,000 festival attendees and added more than 2,000 new members to the Be The Match Registry. We also produced a social media awareness campaign featuring one of our own employees, who is a cofounder of the Pride Employee Resource Group at Be The Match and a recent blood stem cell donor.”
In 2020 as blood banks became desperate for donations during the early days of the COVID-19 pandemic, the FDA changed its policy and required MSM to be abstinent for 3 months instead of 1 year before giving blood. (Prior to December 2014, any man who’d had sex with a man, even once, was indefinitely banned from giving blood.)
The 3-month policy instituted in 2020 drew fire from critics such as the American Medical Association, which noted the regulation treated men differently if they had unprotected sex with a single man versus with multiple women.
Now, the FDA is proposing that it once again change the policy about blood donations: It is recommending that there be no special polices regarding MSM. “All prospective donors who report having a new sexual partner or more than one sexual partner and had anal sex in the past 3 months would be deferred from donation.”
Under the proposal, anyone who’s ever had HIV will not be able to donate. (They can’t donate stem cells either.) And the FDA proposes restrictions on those who take pre-exposure prophylaxis or postexposure prophylaxis for HIV.
Margolis, of Be the Match, noted that some members of the LGBTQ community may not be able to donate to Be The Match BioTherapies, which works with cell and gene therapy developers worldwide to provide cellular starting material. “These therapies may have different requirements than those for blood stem-cell transplants. Men who have had sex with men in the past 5 years or women who have had sex with a man who has had sex with a man in the past 5 years may not be able to donate to Be The Match BioTherapies. While we understand this could be upsetting or frustrating for someone who desires to be a part of these therapies, we are committed to following medical guidelines and regulations, while also advocating for our donors and the LBGTQIA+ community as a whole.”
MSM aren’t the only target of outreach by proponents of stem cell donation. In 2019, UT Southwestern’s Dr. Adkins and colleagues wrote a commentary in Bone Marrow Transplantation that called for bone marrow donation centers to do more to be welcoming to transgender donors. “The largest age group identifying as transgender is 18-24 years of life, which overlaps considerably with the population of hematopoietic stem cell donors, which tend to be younger individuals,” the researchers wrote.
The transgender community was “simply overlooked,” Dr. Adkins said. Since then, as he pointed out, things have changed. Now, Be the Match’s website notes that “members of the LGBTQIA+ community CAN join the registry and donate.” The organization says that “for medical reasons, everyone is asked to provide their sex assigned at birth when they register. Should you be called as a match, pronouns and gender identity are respected throughout the process.”
In addition, the site says people on prescription hormone therapy are not excluded from joining the registry. Patients who have undergone surgery within the last 12 months, including sex-reassignment procedures, “will be asked about the current status of their recovery and whether they are still seeing a physician for follow-up in regards to the surgery.”
What’s next? Dr. Fingrut said he expects the lifting of strict rules about MSM and blood donation will boost stem cell donation in the community.
There seems to be plenty of room for more outreach. Cole Williams, founder of Pride & Plasma, which advocates for allowing gay men to give blood, suggested in an interview that advocates who want to increase stem cell donation in the LGBTQ community reach out to its community centers, health organizations, providers, and clinics.
So far, though, “I haven’t seen a big call for registration of any individuals unless they have a personal relation to bone marrow donation,” he said.
Dr. Fingrut and Dr. Adkins report no disclosures.
In fact, gay men have been able to donate stem cells in the United States since 2015. That’s when National Marrow Donor Program’s Be the Match registry lifted restrictions on men who have sex with men (MSM).
Physicians say advocacy is still necessary, because LGBTQ people may assume they can’t donate or be wary of clinicians. “The LGBTQIA+ population in general has experienced a lot of issues with the medical-industrial complex in terms of discrimination and inappropriate care,” said UT Southwestern Medical Center pathologist Brian Adkins, MD, who manages the blood bank at Children’s Health in Dallas, in an interview. “There’s a weariness there that may produce some hesitancy to interact with the donation process.”
An estimated 6.8 million people give blood in the United States each year, and an estimated 9 million people are registered as potential stem cell donors. A total of 22,013 hematopoietic cell transplantation procedures were performed in 2020, according to the U.S. Health Resources and Services Administration.
Expanding the number of LGBTQ donors, especially those born as biological males, could pay major dividends. As Dr. Adkins noted, the ideal stem cell donor is young – Be the Match says doctors generally prefer donors aged 18-35 – and male. According to a 2021 Gallup Poll, 21% of those born from 1997 to 2003 (Generation Z) say they’re LGBTQ, as do 11% of those born from 1981 to 1996 (Millennials).
In North America, the most extensive outreach to the LGBTQ community about stem cell donation has been launched in Canada. There, an organization called Stem Cell Club focuses on encouraging college students and other young people to register as potential stem cell donors.
Stem Cell Club has several campaigns aimed at ethnic minority groups, and its Saving Lives With Pride project focuses on MSM. The project’s web page includes testimonials from a woman whose life was saved by an unrelated gay male donor and from a gay male nurse who recovered from blood cancer thanks to a stem cell donation. The site also includes videos about stem cell donation featuring LGBTQ young people and Canadian hematologists.
“Our specialized collection center will treat donors with the highest levels of respect and courtesy, indeed as heroes of their unselfish gift that can truly save a life,” says Ottawa Hospital transplant hematologist David Allan, MD, in one of the videos.
Stem Cell Club was founded by transplant hematologist Warren Fingrut, MD, a research fellow at Memorial Sloan Kettering Cancer Center. In an interview, he said the organization’s LGBTQ project has promoted stem cell donation at several annual gay pride events and will continue the outreach this coming summer. In 2018 and 2019, advocates recruited 354 potential stem-cell donors (40% male, 42 non-White) at five pride events, Dr. Fingrut and colleagues reported last year in the journal Bone Marrow Transplantation.
For a new study, researchers interviewed 37 gay and bisexual men from five Canadian provinces about stem cell donation. Dr. Fingrut and colleagues reported the findings in February in an abstract at the Transplantation & Cellular Therapy Meetings.
Most participants didn’t know they “are eligible to donate stem cells, with many confusing stem cell versus blood donor eligibility criteria,” the researchers reported. According to Dr. Fingrut, some of the men “felt they were treated as second-class citizens, and that translated into frustration and decreased motivation to donate. There were concerns that they would be treated as though they shouldn’t be there.”
Canada has allowed gay men to donate stem cells for at least 10 years, Dr. Fingrut said. In 2022, Canadian officials said blood banks would no longer require MSM donors to have been abstinent from sex for 3 months, the BBC reported. However, donors will be asked about high-risk sexual behaviors.
The United States, where HIV spread through the blood supply during the early years of the AIDS pandemic and killed thousands of hemophiliacs, has much been slower to change its policies. For decades, starting in the 1980s, both blood banks and stem cell donation programs chose to lower the risk by turning away MSM donors.
Policies only began to change in recent years. Be the Match’s registry led the way by welcoming MSM in 2015. Stem cell donations go through more extensive testing than blood donations, Dr. Adkins said, so it’s more likely that HIV will be screened out. Also, he said, officials probably realized “it was necessary to widen the donor pool in order to best serve the patients” because it’s so hard to find matched stem-cell donors.
Be the Match has also stepped up its outreach to the LGBTQ community. “During Pride Month in 2022, Be The Match sponsored booths at events in 12 major markets from coast to coast,” said Jamie Margolis, senior vice president of Donor Services. “These efforts enabled us to increase awareness among more than 500,000 festival attendees and added more than 2,000 new members to the Be The Match Registry. We also produced a social media awareness campaign featuring one of our own employees, who is a cofounder of the Pride Employee Resource Group at Be The Match and a recent blood stem cell donor.”
In 2020 as blood banks became desperate for donations during the early days of the COVID-19 pandemic, the FDA changed its policy and required MSM to be abstinent for 3 months instead of 1 year before giving blood. (Prior to December 2014, any man who’d had sex with a man, even once, was indefinitely banned from giving blood.)
The 3-month policy instituted in 2020 drew fire from critics such as the American Medical Association, which noted the regulation treated men differently if they had unprotected sex with a single man versus with multiple women.
Now, the FDA is proposing that it once again change the policy about blood donations: It is recommending that there be no special polices regarding MSM. “All prospective donors who report having a new sexual partner or more than one sexual partner and had anal sex in the past 3 months would be deferred from donation.”
Under the proposal, anyone who’s ever had HIV will not be able to donate. (They can’t donate stem cells either.) And the FDA proposes restrictions on those who take pre-exposure prophylaxis or postexposure prophylaxis for HIV.
Margolis, of Be the Match, noted that some members of the LGBTQ community may not be able to donate to Be The Match BioTherapies, which works with cell and gene therapy developers worldwide to provide cellular starting material. “These therapies may have different requirements than those for blood stem-cell transplants. Men who have had sex with men in the past 5 years or women who have had sex with a man who has had sex with a man in the past 5 years may not be able to donate to Be The Match BioTherapies. While we understand this could be upsetting or frustrating for someone who desires to be a part of these therapies, we are committed to following medical guidelines and regulations, while also advocating for our donors and the LBGTQIA+ community as a whole.”
MSM aren’t the only target of outreach by proponents of stem cell donation. In 2019, UT Southwestern’s Dr. Adkins and colleagues wrote a commentary in Bone Marrow Transplantation that called for bone marrow donation centers to do more to be welcoming to transgender donors. “The largest age group identifying as transgender is 18-24 years of life, which overlaps considerably with the population of hematopoietic stem cell donors, which tend to be younger individuals,” the researchers wrote.
The transgender community was “simply overlooked,” Dr. Adkins said. Since then, as he pointed out, things have changed. Now, Be the Match’s website notes that “members of the LGBTQIA+ community CAN join the registry and donate.” The organization says that “for medical reasons, everyone is asked to provide their sex assigned at birth when they register. Should you be called as a match, pronouns and gender identity are respected throughout the process.”
In addition, the site says people on prescription hormone therapy are not excluded from joining the registry. Patients who have undergone surgery within the last 12 months, including sex-reassignment procedures, “will be asked about the current status of their recovery and whether they are still seeing a physician for follow-up in regards to the surgery.”
What’s next? Dr. Fingrut said he expects the lifting of strict rules about MSM and blood donation will boost stem cell donation in the community.
There seems to be plenty of room for more outreach. Cole Williams, founder of Pride & Plasma, which advocates for allowing gay men to give blood, suggested in an interview that advocates who want to increase stem cell donation in the LGBTQ community reach out to its community centers, health organizations, providers, and clinics.
So far, though, “I haven’t seen a big call for registration of any individuals unless they have a personal relation to bone marrow donation,” he said.
Dr. Fingrut and Dr. Adkins report no disclosures.
High cost and demand for old cancer drug sparks crisis
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
Gloom lifting as MCL treatments evolve
Traditionally, MCL has had a notoriously poor prognosis and is still impossible to cure. But survival rates are rising thanks to better treatments, the review authors wrote, and even relapsed/refractory patients have a growing number of options that can potentially give them extra years of life.
“Prognosis has certainly changed in past 10 years. We have been able to have an excellent control of disease, and patients are living longer, even past the 8- or 10-year mark,” Moffit Cancer Center/Memorial Healthcare System hematologist-oncologist Jose Sandoval‐Sus, MD, said in an interview. He is corresponding author of the review, which appeared in the October issue of Current Oncology Reports.
MCL – which affects cells in the mantle zone of lymph nodes – is rare. It usually strikes older men, often presents at an advanced stage, and accounts for 6%-8% of non-Hodgkin lymphomas in the United States.
Prognoses are improving. The review highlights a study released earlier this year that found that median 5-year overall survival has increased from 68.8% (2002-2009) to 81.6% (2010-2015).
Now, the review notes, there are several first-line chemotherapy options that combine agents with rituximab such as rituximab/bendamustine, which “has generally been established as an effective treatment for MCL at first relapse in patients who are bendamustine naive when compared to other chemotherapy agents.”
Other treatments include rituximab, bortezomib, cyclophosphamide, doxorubicin, vincristine, and prednisolone; rituximab, bendamustine and cytarabine; and rituximab, gemcitabine, and oxaliplatin.
“I think of rituximab as a medication of maintenance, either after autologous stem cell transplant or even in patients who have not been through transplant,” Dr. Sandoval‐Sus said. “As maintenance, it really has improved outcomes for these patients.”
But the first step before treatment, he said, is to explore prognostic factors such as alterations on the TP53 gene that “really dictate a lot in terms of the prognosis of patients.” As the review notes, these alterations – either bi-allelic del17p or TP53 mutations – “are associated with poor outcomes after frontline and salvage regimens, including targeted agents such as Burton’s tyrosine kinase inhibitors (BTKis).”
These patients, who make up about 20% of those with MCL, also are most unlikely to benefit from autologous stem cell transplantation, Dr. Sandoval‐Sus said.
What about refracted/relapsed (R/R) cases? BTKis have been a major advance for these patients, he said. However, choosing the best drug can be a challenge. As the review notes, “all approved BTKis for R/R MCL seem to have similar clinical outcomes based on identical mechanism of action, and there are no prospective trials comparing these agents in a head-to-head fashion.”
The authors added that “we wonder if AEs [adverse events] could be decreased by using combinations based on new generation BTKi, but it is still a question that needs to be resolved in the clinical trial arena.”
Stem cell transplants may be an option, the review said, but “in practice the clinical benefit ... is limited to single-center series or small multi-institutional registries with few prospective studies.”
Then there’s CAR-T cell therapy, the game-changer. A type called brexucabtagene autoleucel (Brexu-cel) is now approved in MCL, the review authors wrote, and real-world data “serve as a platform to expand CAR-T therapy to more R/R MCL patients that do not fit the strict inclusion criteria of the studies (e.g., controlled comorbidities and worse performance status)... We strongly recommend early referral of these patients to accredited institutions with ample cellular therapy experience, including high-risk MCL patients (e.g., blastoid/pleomorphic morphology, biallelic del17p, TP53 mutations) so an appropriate bridging strategy and a CAR-T cell roadmap is planned with the patient and caretakers.”
Some researchers are exploring combination treatment with both BTKis and CAR T-cell therapy, “which may be considered for patients with R/R MCL who are naive to both CAR T-cell and BTKi therapy, because combination therapy may increase treatment efficacy,” wrote the authors of another review that appeared in the October issue of Current Oncology Reports. “Based on limited data in patients with CLL, BTKi therapy may be initiated as bridging therapy and continued during lymphodepletion prior to CAR T-cell infusion”
What’s next? Multiple treatments are in the research stage, Dr. Sandoval‐Sus said. “There are a lot of things in development that are really incredible.”
Reversible BTKis, for example, appear to be effective at controlling disease and are well-tolerated, he said. “And we are awaiting the results of clinical trials of targeted therapies.”
For now, he said, the best advice for hematologists is to gain a full understanding of a patient’s MCL, in order to provide the most appropriate treatment. Community oncologists should get at least one second opinion from an academic center or other clinic that treats these kinds of lymphomas, he said, and molecular tests are crucial. A discussion about stem cell transplantation after remission is a good idea, he said, and so is an exploration of clinical trials “from the get-go.”
“In patients who relapse and have high-risk features, they should be started on a BTKi inhibitor for the most part,” he said, “although we need to weigh risks and benefits between the side effects of different BTKi inhibitors. And they should be referred earlier to a CAR T cell therapy center, so they can discuss the benefits and see if they’re an appropriate patient. I think patients are being referred a little bit too late in the second- or third-line setting.”
What about CAR T therapy as a first-line therapy? It’s not FDA-approved, Dr. Sandoval‐Sus said, and “definitely not a standard of care.” But clinical trials are exploring the idea, he said. As for messages to patients, Dr. Sandoval-Sus said he would tell them that MCL is not yet curable, “but the future is very bright.”
Dr. Sandoval-Sus declared advisory board relationships with Seagen, Incyte, Janssen, ADC Therapeutics, TG therapeutics, and Genmab. The other review authors had no disclosures.
Traditionally, MCL has had a notoriously poor prognosis and is still impossible to cure. But survival rates are rising thanks to better treatments, the review authors wrote, and even relapsed/refractory patients have a growing number of options that can potentially give them extra years of life.
“Prognosis has certainly changed in past 10 years. We have been able to have an excellent control of disease, and patients are living longer, even past the 8- or 10-year mark,” Moffit Cancer Center/Memorial Healthcare System hematologist-oncologist Jose Sandoval‐Sus, MD, said in an interview. He is corresponding author of the review, which appeared in the October issue of Current Oncology Reports.
MCL – which affects cells in the mantle zone of lymph nodes – is rare. It usually strikes older men, often presents at an advanced stage, and accounts for 6%-8% of non-Hodgkin lymphomas in the United States.
Prognoses are improving. The review highlights a study released earlier this year that found that median 5-year overall survival has increased from 68.8% (2002-2009) to 81.6% (2010-2015).
Now, the review notes, there are several first-line chemotherapy options that combine agents with rituximab such as rituximab/bendamustine, which “has generally been established as an effective treatment for MCL at first relapse in patients who are bendamustine naive when compared to other chemotherapy agents.”
Other treatments include rituximab, bortezomib, cyclophosphamide, doxorubicin, vincristine, and prednisolone; rituximab, bendamustine and cytarabine; and rituximab, gemcitabine, and oxaliplatin.
“I think of rituximab as a medication of maintenance, either after autologous stem cell transplant or even in patients who have not been through transplant,” Dr. Sandoval‐Sus said. “As maintenance, it really has improved outcomes for these patients.”
But the first step before treatment, he said, is to explore prognostic factors such as alterations on the TP53 gene that “really dictate a lot in terms of the prognosis of patients.” As the review notes, these alterations – either bi-allelic del17p or TP53 mutations – “are associated with poor outcomes after frontline and salvage regimens, including targeted agents such as Burton’s tyrosine kinase inhibitors (BTKis).”
These patients, who make up about 20% of those with MCL, also are most unlikely to benefit from autologous stem cell transplantation, Dr. Sandoval‐Sus said.
What about refracted/relapsed (R/R) cases? BTKis have been a major advance for these patients, he said. However, choosing the best drug can be a challenge. As the review notes, “all approved BTKis for R/R MCL seem to have similar clinical outcomes based on identical mechanism of action, and there are no prospective trials comparing these agents in a head-to-head fashion.”
The authors added that “we wonder if AEs [adverse events] could be decreased by using combinations based on new generation BTKi, but it is still a question that needs to be resolved in the clinical trial arena.”
Stem cell transplants may be an option, the review said, but “in practice the clinical benefit ... is limited to single-center series or small multi-institutional registries with few prospective studies.”
Then there’s CAR-T cell therapy, the game-changer. A type called brexucabtagene autoleucel (Brexu-cel) is now approved in MCL, the review authors wrote, and real-world data “serve as a platform to expand CAR-T therapy to more R/R MCL patients that do not fit the strict inclusion criteria of the studies (e.g., controlled comorbidities and worse performance status)... We strongly recommend early referral of these patients to accredited institutions with ample cellular therapy experience, including high-risk MCL patients (e.g., blastoid/pleomorphic morphology, biallelic del17p, TP53 mutations) so an appropriate bridging strategy and a CAR-T cell roadmap is planned with the patient and caretakers.”
Some researchers are exploring combination treatment with both BTKis and CAR T-cell therapy, “which may be considered for patients with R/R MCL who are naive to both CAR T-cell and BTKi therapy, because combination therapy may increase treatment efficacy,” wrote the authors of another review that appeared in the October issue of Current Oncology Reports. “Based on limited data in patients with CLL, BTKi therapy may be initiated as bridging therapy and continued during lymphodepletion prior to CAR T-cell infusion”
What’s next? Multiple treatments are in the research stage, Dr. Sandoval‐Sus said. “There are a lot of things in development that are really incredible.”
Reversible BTKis, for example, appear to be effective at controlling disease and are well-tolerated, he said. “And we are awaiting the results of clinical trials of targeted therapies.”
For now, he said, the best advice for hematologists is to gain a full understanding of a patient’s MCL, in order to provide the most appropriate treatment. Community oncologists should get at least one second opinion from an academic center or other clinic that treats these kinds of lymphomas, he said, and molecular tests are crucial. A discussion about stem cell transplantation after remission is a good idea, he said, and so is an exploration of clinical trials “from the get-go.”
“In patients who relapse and have high-risk features, they should be started on a BTKi inhibitor for the most part,” he said, “although we need to weigh risks and benefits between the side effects of different BTKi inhibitors. And they should be referred earlier to a CAR T cell therapy center, so they can discuss the benefits and see if they’re an appropriate patient. I think patients are being referred a little bit too late in the second- or third-line setting.”
What about CAR T therapy as a first-line therapy? It’s not FDA-approved, Dr. Sandoval‐Sus said, and “definitely not a standard of care.” But clinical trials are exploring the idea, he said. As for messages to patients, Dr. Sandoval-Sus said he would tell them that MCL is not yet curable, “but the future is very bright.”
Dr. Sandoval-Sus declared advisory board relationships with Seagen, Incyte, Janssen, ADC Therapeutics, TG therapeutics, and Genmab. The other review authors had no disclosures.
Traditionally, MCL has had a notoriously poor prognosis and is still impossible to cure. But survival rates are rising thanks to better treatments, the review authors wrote, and even relapsed/refractory patients have a growing number of options that can potentially give them extra years of life.
“Prognosis has certainly changed in past 10 years. We have been able to have an excellent control of disease, and patients are living longer, even past the 8- or 10-year mark,” Moffit Cancer Center/Memorial Healthcare System hematologist-oncologist Jose Sandoval‐Sus, MD, said in an interview. He is corresponding author of the review, which appeared in the October issue of Current Oncology Reports.
MCL – which affects cells in the mantle zone of lymph nodes – is rare. It usually strikes older men, often presents at an advanced stage, and accounts for 6%-8% of non-Hodgkin lymphomas in the United States.
Prognoses are improving. The review highlights a study released earlier this year that found that median 5-year overall survival has increased from 68.8% (2002-2009) to 81.6% (2010-2015).
Now, the review notes, there are several first-line chemotherapy options that combine agents with rituximab such as rituximab/bendamustine, which “has generally been established as an effective treatment for MCL at first relapse in patients who are bendamustine naive when compared to other chemotherapy agents.”
Other treatments include rituximab, bortezomib, cyclophosphamide, doxorubicin, vincristine, and prednisolone; rituximab, bendamustine and cytarabine; and rituximab, gemcitabine, and oxaliplatin.
“I think of rituximab as a medication of maintenance, either after autologous stem cell transplant or even in patients who have not been through transplant,” Dr. Sandoval‐Sus said. “As maintenance, it really has improved outcomes for these patients.”
But the first step before treatment, he said, is to explore prognostic factors such as alterations on the TP53 gene that “really dictate a lot in terms of the prognosis of patients.” As the review notes, these alterations – either bi-allelic del17p or TP53 mutations – “are associated with poor outcomes after frontline and salvage regimens, including targeted agents such as Burton’s tyrosine kinase inhibitors (BTKis).”
These patients, who make up about 20% of those with MCL, also are most unlikely to benefit from autologous stem cell transplantation, Dr. Sandoval‐Sus said.
What about refracted/relapsed (R/R) cases? BTKis have been a major advance for these patients, he said. However, choosing the best drug can be a challenge. As the review notes, “all approved BTKis for R/R MCL seem to have similar clinical outcomes based on identical mechanism of action, and there are no prospective trials comparing these agents in a head-to-head fashion.”
The authors added that “we wonder if AEs [adverse events] could be decreased by using combinations based on new generation BTKi, but it is still a question that needs to be resolved in the clinical trial arena.”
Stem cell transplants may be an option, the review said, but “in practice the clinical benefit ... is limited to single-center series or small multi-institutional registries with few prospective studies.”
Then there’s CAR-T cell therapy, the game-changer. A type called brexucabtagene autoleucel (Brexu-cel) is now approved in MCL, the review authors wrote, and real-world data “serve as a platform to expand CAR-T therapy to more R/R MCL patients that do not fit the strict inclusion criteria of the studies (e.g., controlled comorbidities and worse performance status)... We strongly recommend early referral of these patients to accredited institutions with ample cellular therapy experience, including high-risk MCL patients (e.g., blastoid/pleomorphic morphology, biallelic del17p, TP53 mutations) so an appropriate bridging strategy and a CAR-T cell roadmap is planned with the patient and caretakers.”
Some researchers are exploring combination treatment with both BTKis and CAR T-cell therapy, “which may be considered for patients with R/R MCL who are naive to both CAR T-cell and BTKi therapy, because combination therapy may increase treatment efficacy,” wrote the authors of another review that appeared in the October issue of Current Oncology Reports. “Based on limited data in patients with CLL, BTKi therapy may be initiated as bridging therapy and continued during lymphodepletion prior to CAR T-cell infusion”
What’s next? Multiple treatments are in the research stage, Dr. Sandoval‐Sus said. “There are a lot of things in development that are really incredible.”
Reversible BTKis, for example, appear to be effective at controlling disease and are well-tolerated, he said. “And we are awaiting the results of clinical trials of targeted therapies.”
For now, he said, the best advice for hematologists is to gain a full understanding of a patient’s MCL, in order to provide the most appropriate treatment. Community oncologists should get at least one second opinion from an academic center or other clinic that treats these kinds of lymphomas, he said, and molecular tests are crucial. A discussion about stem cell transplantation after remission is a good idea, he said, and so is an exploration of clinical trials “from the get-go.”
“In patients who relapse and have high-risk features, they should be started on a BTKi inhibitor for the most part,” he said, “although we need to weigh risks and benefits between the side effects of different BTKi inhibitors. And they should be referred earlier to a CAR T cell therapy center, so they can discuss the benefits and see if they’re an appropriate patient. I think patients are being referred a little bit too late in the second- or third-line setting.”
What about CAR T therapy as a first-line therapy? It’s not FDA-approved, Dr. Sandoval‐Sus said, and “definitely not a standard of care.” But clinical trials are exploring the idea, he said. As for messages to patients, Dr. Sandoval-Sus said he would tell them that MCL is not yet curable, “but the future is very bright.”
Dr. Sandoval-Sus declared advisory board relationships with Seagen, Incyte, Janssen, ADC Therapeutics, TG therapeutics, and Genmab. The other review authors had no disclosures.
CAR T-cell therapy neurotoxicity linked to NfL elevations
“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.
“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.
CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.
Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.
NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.
To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.
The patients had a median age of 64 and were 40% female.
Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.
Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.
A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).
Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.
However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.
The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
Interest in NfL levels on the rise
NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.
Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.
“Future studies will explore validating NfL for ICANS and additional indications,” he said.
ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.
The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.
Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.
“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
Limitations: Validation, preventive measures needed
Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.
“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.
The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.
“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”
A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.
“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”
Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.
“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.
“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.
CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.
Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.
NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.
To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.
The patients had a median age of 64 and were 40% female.
Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.
Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.
A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).
Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.
However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.
The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
Interest in NfL levels on the rise
NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.
Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.
“Future studies will explore validating NfL for ICANS and additional indications,” he said.
ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.
The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.
Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.
“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
Limitations: Validation, preventive measures needed
Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.
“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.
The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.
“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”
A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.
“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”
Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.
“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.
“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.
CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.
Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.
NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.
To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.
The patients had a median age of 64 and were 40% female.
Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.
Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.
A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).
Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.
However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.
The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
Interest in NfL levels on the rise
NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.
Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.
“Future studies will explore validating NfL for ICANS and additional indications,” he said.
ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.
The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.
Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.
“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
Limitations: Validation, preventive measures needed
Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.
“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.
The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.
“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”
A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.
“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”
Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.
FROM JAMA ONCOLOGY
Novel approach brings hospice-bound MM patient into remission
In a case that researchers hope might pave the way for similar responses, a hospice-bound relapsed/refractory multiple myeloma (RRMM) patient who relapsed after chimeric antigen receptor (CAR) T-cell therapy was brought back into remission with the help of next-generation genomic sequencing, targeted molecular analysis and a novel combination of MAP kinase (MAPK)–inhibiting drugs.
“We have shown that comprehensive molecular profiling of advanced myeloma patients may provide critical information to guide treatment beyond standard of care,” senior author Alessandro Lagana, PhD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.
“This represents proof of concept that, while not curative, targeted molecules may serve as potential bridging therapies to clinical trial enrollment,” the authors further report in the case study, published recently in the Journal of Hematology & Oncology.
The use of B-cell maturation antigen (BCMA) CAR T-cell therapy approaches has transformed the treatment of multiple myeloma and leukemias, resulting in high response rates. However, most patients ultimately relapse, and no clear treatment options beyond CAR T therapy are established.
Such was the case for a 61-year old patient described in the study, who had relapsed 6 months after undergoing anti-BCMA CAR T-cell therapy and progressed after being salvaged for a short period with autologous stem cell transplantation. The patient had developed skin extramedullary disease, manifested as subcutaneous nodules.
“The subcutaneous skin lesions in lower extremities made him [ineligible] for another clinical trial and left him with no options,” Dr. Lagana said.
Using next-generation whole-exome sequencing, Dr. Lagana and colleagues had observed that a previously identified BRAF V600E–dominant subclone had persisted, despite the CAR T-cell treatment, in the patient’s bone marrow and cutaneous plasmacytoma.
The finding was not uncommon. More than half of RRMM patients (about 53%) show emerging clones with mutations within the MAPK signaling pathway, and in about 7% of patients, those include BRAF V600E, which can be targeted, the authors noted.
Further assessment of the patient’s CD138-positive MM cells using western blot signaling pathway analysis looking at DNA and RNA markers did indeed show an increase in MAPK signaling as a consequence of the mutation. This suggested a potential benefit of triple MAPK inhibition, compared with standard strategies.
Based on that information and on insights the researchers had gained from previous research, they implemented the novel, orally administered triple-combination treatment strategy, consisting of monomeric inhibition of BRAF dabrafenib (100 mg, twice daily), as well as dimeric inhibition with the multi–kinase inhibitor regorafenib (40 mg, once daily) and a MEK inhibitor (trametinib, 1.5 mg, for 21/28 days daily).
Of note, previous efforts using only monomeric inhibition of BRAF have not shown much success, but early data has shown some potential, with the inclusion of dimeric inhibition.
“Monomeric inhibition of BRAF has been attempted in patients with V600E, but the efficacy has been limited, likely due to feedback activation of the MAPK pathway via induction of BRAF dimer formation,” Dr. Lagana explained.
Meanwhile, “previous in vitro data from our colleagues at Mount Sinai has shown that inhibition of both monomeric and dimeric forms of BRAF in combination with MEK inhibition can overcome the negative feedback and lead to more efficacious and tolerable treatment,” he said.
With the treatment, the patient achieved a very good partial response for 110 days, with prompt reduction of the subcutaneous skin lesions and an 80% reduction in lambda free light chain (27.5 mg/L).
The triple-drug combination was well tolerated with minimal side effects, primarily involving grade 1 fatigue, and the patient was able to carry out activities of daily living and return to work.
“The triple inhibition allowed us to use less of each drug, which resulted in a well-tolerated regimen without any significant side effects,” Dr. Lagana said.
While the patient relapsed about 3 months later, there was, importantly, no recurrence of the subcutaneous nodules.
“We believe that the triple MAPK inhibition completely eradicated the disease clones driving the extramedullary disease,” Dr. Lagana said.
The therapy meanwhile enabled the patient to bridge to a new clinical trial, where he went into complete remission, and still was as of Sept. 29.
“To our knowledge, this was the first reported successful case of this treatment in an RRMM patient,” Dr. Lagana explained.
Case suggests ‘hope’ for relapsing patients
Importantly, currently many patients in the same position may wind up going to hospice, until such targeted medicine gains momentum, coauthor Samir Parekh, MD, a professor of hematology-oncology at the Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, said in an interview.
“As precision medicine is in its infancy in myeloma, these patients are not routinely sequenced for drug options that may be identified by next-generation sequencing,” said Dr. Parekh.
But for clinicians, the message of this case should be that “there is hope for patients relapsing after CAR T,” he added.
“Precision medicine approaches may be applicable even for this relapsed patient population,” he added. “MAP kinase mutations are common and drugs targeting them may be useful in myeloma.”
Noting that “the infrastructure to test and guide application of these therapies needs to be developed for myeloma, Dr. Parekh predicted that, “in the future, more effective MAPK inhibitors and other mutation or RNA-seq guided therapies will be applicable and hopefully provide more durable remissions.”
Approach may help address unmet need
Until then, however, treatment for patients who relapse after CAR-T and BCMA-targeted therapies has emerged as a significant unmet need. Therefore, this case highlights an important potential strategy, said Hans Lee, MD, an associate professor in the department of lymphoma/myeloma, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, commenting on the study.
“This case report provides impetus for oncologists to strongly consider performing next-generation sequencing on myeloma tumor samples to look for potential actionable mutations, such as those in the MAPK pathway – which are common in myeloma,” he said. “With limited treatment options in the post–CAR T and post-BCMA setting, identifying such actional mutations may at least provide a bridge to other effective therapies available through clinical trials such as this patient’s case.”
Dr. Lee noted that key caveats include the fact that most physicians currently don’t have access to the type of next-generation sequencing and drug sensitivity testing used in the study.
Nevertheless, considering the limited options in the post–CAR T and post-BCMA setting, “the successful use of triple MAPK pathway inhibition through monomeric and dimeric inhibition of BRAF and MEK inhibition warrants further study in multiple myeloma in a clinical trial,” he said.
Dr. Lagana and associates are doing just that.
“We are about to launch the clinical trial, where we will match advanced RRMM patients with potential targeted treatments using different DNA and RNA markers,” Dr. Lagana said.
Dr. Lagana and Dr. Parekh had no disclosures to report. Three study coauthors reported receiving research grants or consulting fees from numerous pharmaceutical companies.
In a case that researchers hope might pave the way for similar responses, a hospice-bound relapsed/refractory multiple myeloma (RRMM) patient who relapsed after chimeric antigen receptor (CAR) T-cell therapy was brought back into remission with the help of next-generation genomic sequencing, targeted molecular analysis and a novel combination of MAP kinase (MAPK)–inhibiting drugs.
“We have shown that comprehensive molecular profiling of advanced myeloma patients may provide critical information to guide treatment beyond standard of care,” senior author Alessandro Lagana, PhD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.
“This represents proof of concept that, while not curative, targeted molecules may serve as potential bridging therapies to clinical trial enrollment,” the authors further report in the case study, published recently in the Journal of Hematology & Oncology.
The use of B-cell maturation antigen (BCMA) CAR T-cell therapy approaches has transformed the treatment of multiple myeloma and leukemias, resulting in high response rates. However, most patients ultimately relapse, and no clear treatment options beyond CAR T therapy are established.
Such was the case for a 61-year old patient described in the study, who had relapsed 6 months after undergoing anti-BCMA CAR T-cell therapy and progressed after being salvaged for a short period with autologous stem cell transplantation. The patient had developed skin extramedullary disease, manifested as subcutaneous nodules.
“The subcutaneous skin lesions in lower extremities made him [ineligible] for another clinical trial and left him with no options,” Dr. Lagana said.
Using next-generation whole-exome sequencing, Dr. Lagana and colleagues had observed that a previously identified BRAF V600E–dominant subclone had persisted, despite the CAR T-cell treatment, in the patient’s bone marrow and cutaneous plasmacytoma.
The finding was not uncommon. More than half of RRMM patients (about 53%) show emerging clones with mutations within the MAPK signaling pathway, and in about 7% of patients, those include BRAF V600E, which can be targeted, the authors noted.
Further assessment of the patient’s CD138-positive MM cells using western blot signaling pathway analysis looking at DNA and RNA markers did indeed show an increase in MAPK signaling as a consequence of the mutation. This suggested a potential benefit of triple MAPK inhibition, compared with standard strategies.
Based on that information and on insights the researchers had gained from previous research, they implemented the novel, orally administered triple-combination treatment strategy, consisting of monomeric inhibition of BRAF dabrafenib (100 mg, twice daily), as well as dimeric inhibition with the multi–kinase inhibitor regorafenib (40 mg, once daily) and a MEK inhibitor (trametinib, 1.5 mg, for 21/28 days daily).
Of note, previous efforts using only monomeric inhibition of BRAF have not shown much success, but early data has shown some potential, with the inclusion of dimeric inhibition.
“Monomeric inhibition of BRAF has been attempted in patients with V600E, but the efficacy has been limited, likely due to feedback activation of the MAPK pathway via induction of BRAF dimer formation,” Dr. Lagana explained.
Meanwhile, “previous in vitro data from our colleagues at Mount Sinai has shown that inhibition of both monomeric and dimeric forms of BRAF in combination with MEK inhibition can overcome the negative feedback and lead to more efficacious and tolerable treatment,” he said.
With the treatment, the patient achieved a very good partial response for 110 days, with prompt reduction of the subcutaneous skin lesions and an 80% reduction in lambda free light chain (27.5 mg/L).
The triple-drug combination was well tolerated with minimal side effects, primarily involving grade 1 fatigue, and the patient was able to carry out activities of daily living and return to work.
“The triple inhibition allowed us to use less of each drug, which resulted in a well-tolerated regimen without any significant side effects,” Dr. Lagana said.
While the patient relapsed about 3 months later, there was, importantly, no recurrence of the subcutaneous nodules.
“We believe that the triple MAPK inhibition completely eradicated the disease clones driving the extramedullary disease,” Dr. Lagana said.
The therapy meanwhile enabled the patient to bridge to a new clinical trial, where he went into complete remission, and still was as of Sept. 29.
“To our knowledge, this was the first reported successful case of this treatment in an RRMM patient,” Dr. Lagana explained.
Case suggests ‘hope’ for relapsing patients
Importantly, currently many patients in the same position may wind up going to hospice, until such targeted medicine gains momentum, coauthor Samir Parekh, MD, a professor of hematology-oncology at the Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, said in an interview.
“As precision medicine is in its infancy in myeloma, these patients are not routinely sequenced for drug options that may be identified by next-generation sequencing,” said Dr. Parekh.
But for clinicians, the message of this case should be that “there is hope for patients relapsing after CAR T,” he added.
“Precision medicine approaches may be applicable even for this relapsed patient population,” he added. “MAP kinase mutations are common and drugs targeting them may be useful in myeloma.”
Noting that “the infrastructure to test and guide application of these therapies needs to be developed for myeloma, Dr. Parekh predicted that, “in the future, more effective MAPK inhibitors and other mutation or RNA-seq guided therapies will be applicable and hopefully provide more durable remissions.”
Approach may help address unmet need
Until then, however, treatment for patients who relapse after CAR-T and BCMA-targeted therapies has emerged as a significant unmet need. Therefore, this case highlights an important potential strategy, said Hans Lee, MD, an associate professor in the department of lymphoma/myeloma, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, commenting on the study.
“This case report provides impetus for oncologists to strongly consider performing next-generation sequencing on myeloma tumor samples to look for potential actionable mutations, such as those in the MAPK pathway – which are common in myeloma,” he said. “With limited treatment options in the post–CAR T and post-BCMA setting, identifying such actional mutations may at least provide a bridge to other effective therapies available through clinical trials such as this patient’s case.”
Dr. Lee noted that key caveats include the fact that most physicians currently don’t have access to the type of next-generation sequencing and drug sensitivity testing used in the study.
Nevertheless, considering the limited options in the post–CAR T and post-BCMA setting, “the successful use of triple MAPK pathway inhibition through monomeric and dimeric inhibition of BRAF and MEK inhibition warrants further study in multiple myeloma in a clinical trial,” he said.
Dr. Lagana and associates are doing just that.
“We are about to launch the clinical trial, where we will match advanced RRMM patients with potential targeted treatments using different DNA and RNA markers,” Dr. Lagana said.
Dr. Lagana and Dr. Parekh had no disclosures to report. Three study coauthors reported receiving research grants or consulting fees from numerous pharmaceutical companies.
In a case that researchers hope might pave the way for similar responses, a hospice-bound relapsed/refractory multiple myeloma (RRMM) patient who relapsed after chimeric antigen receptor (CAR) T-cell therapy was brought back into remission with the help of next-generation genomic sequencing, targeted molecular analysis and a novel combination of MAP kinase (MAPK)–inhibiting drugs.
“We have shown that comprehensive molecular profiling of advanced myeloma patients may provide critical information to guide treatment beyond standard of care,” senior author Alessandro Lagana, PhD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.
“This represents proof of concept that, while not curative, targeted molecules may serve as potential bridging therapies to clinical trial enrollment,” the authors further report in the case study, published recently in the Journal of Hematology & Oncology.
The use of B-cell maturation antigen (BCMA) CAR T-cell therapy approaches has transformed the treatment of multiple myeloma and leukemias, resulting in high response rates. However, most patients ultimately relapse, and no clear treatment options beyond CAR T therapy are established.
Such was the case for a 61-year old patient described in the study, who had relapsed 6 months after undergoing anti-BCMA CAR T-cell therapy and progressed after being salvaged for a short period with autologous stem cell transplantation. The patient had developed skin extramedullary disease, manifested as subcutaneous nodules.
“The subcutaneous skin lesions in lower extremities made him [ineligible] for another clinical trial and left him with no options,” Dr. Lagana said.
Using next-generation whole-exome sequencing, Dr. Lagana and colleagues had observed that a previously identified BRAF V600E–dominant subclone had persisted, despite the CAR T-cell treatment, in the patient’s bone marrow and cutaneous plasmacytoma.
The finding was not uncommon. More than half of RRMM patients (about 53%) show emerging clones with mutations within the MAPK signaling pathway, and in about 7% of patients, those include BRAF V600E, which can be targeted, the authors noted.
Further assessment of the patient’s CD138-positive MM cells using western blot signaling pathway analysis looking at DNA and RNA markers did indeed show an increase in MAPK signaling as a consequence of the mutation. This suggested a potential benefit of triple MAPK inhibition, compared with standard strategies.
Based on that information and on insights the researchers had gained from previous research, they implemented the novel, orally administered triple-combination treatment strategy, consisting of monomeric inhibition of BRAF dabrafenib (100 mg, twice daily), as well as dimeric inhibition with the multi–kinase inhibitor regorafenib (40 mg, once daily) and a MEK inhibitor (trametinib, 1.5 mg, for 21/28 days daily).
Of note, previous efforts using only monomeric inhibition of BRAF have not shown much success, but early data has shown some potential, with the inclusion of dimeric inhibition.
“Monomeric inhibition of BRAF has been attempted in patients with V600E, but the efficacy has been limited, likely due to feedback activation of the MAPK pathway via induction of BRAF dimer formation,” Dr. Lagana explained.
Meanwhile, “previous in vitro data from our colleagues at Mount Sinai has shown that inhibition of both monomeric and dimeric forms of BRAF in combination with MEK inhibition can overcome the negative feedback and lead to more efficacious and tolerable treatment,” he said.
With the treatment, the patient achieved a very good partial response for 110 days, with prompt reduction of the subcutaneous skin lesions and an 80% reduction in lambda free light chain (27.5 mg/L).
The triple-drug combination was well tolerated with minimal side effects, primarily involving grade 1 fatigue, and the patient was able to carry out activities of daily living and return to work.
“The triple inhibition allowed us to use less of each drug, which resulted in a well-tolerated regimen without any significant side effects,” Dr. Lagana said.
While the patient relapsed about 3 months later, there was, importantly, no recurrence of the subcutaneous nodules.
“We believe that the triple MAPK inhibition completely eradicated the disease clones driving the extramedullary disease,” Dr. Lagana said.
The therapy meanwhile enabled the patient to bridge to a new clinical trial, where he went into complete remission, and still was as of Sept. 29.
“To our knowledge, this was the first reported successful case of this treatment in an RRMM patient,” Dr. Lagana explained.
Case suggests ‘hope’ for relapsing patients
Importantly, currently many patients in the same position may wind up going to hospice, until such targeted medicine gains momentum, coauthor Samir Parekh, MD, a professor of hematology-oncology at the Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, said in an interview.
“As precision medicine is in its infancy in myeloma, these patients are not routinely sequenced for drug options that may be identified by next-generation sequencing,” said Dr. Parekh.
But for clinicians, the message of this case should be that “there is hope for patients relapsing after CAR T,” he added.
“Precision medicine approaches may be applicable even for this relapsed patient population,” he added. “MAP kinase mutations are common and drugs targeting them may be useful in myeloma.”
Noting that “the infrastructure to test and guide application of these therapies needs to be developed for myeloma, Dr. Parekh predicted that, “in the future, more effective MAPK inhibitors and other mutation or RNA-seq guided therapies will be applicable and hopefully provide more durable remissions.”
Approach may help address unmet need
Until then, however, treatment for patients who relapse after CAR-T and BCMA-targeted therapies has emerged as a significant unmet need. Therefore, this case highlights an important potential strategy, said Hans Lee, MD, an associate professor in the department of lymphoma/myeloma, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, commenting on the study.
“This case report provides impetus for oncologists to strongly consider performing next-generation sequencing on myeloma tumor samples to look for potential actionable mutations, such as those in the MAPK pathway – which are common in myeloma,” he said. “With limited treatment options in the post–CAR T and post-BCMA setting, identifying such actional mutations may at least provide a bridge to other effective therapies available through clinical trials such as this patient’s case.”
Dr. Lee noted that key caveats include the fact that most physicians currently don’t have access to the type of next-generation sequencing and drug sensitivity testing used in the study.
Nevertheless, considering the limited options in the post–CAR T and post-BCMA setting, “the successful use of triple MAPK pathway inhibition through monomeric and dimeric inhibition of BRAF and MEK inhibition warrants further study in multiple myeloma in a clinical trial,” he said.
Dr. Lagana and associates are doing just that.
“We are about to launch the clinical trial, where we will match advanced RRMM patients with potential targeted treatments using different DNA and RNA markers,” Dr. Lagana said.
Dr. Lagana and Dr. Parekh had no disclosures to report. Three study coauthors reported receiving research grants or consulting fees from numerous pharmaceutical companies.
FROM THE JOURNAL OF HEMATOLOGY & ONCOLOGY
Many die waiting for `last-chance’ therapy
Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.
Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.
About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”
But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.
The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.
The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.
“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”
The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.
For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
Shortage affecting mostly myeloma patients
The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.
The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).
“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”
Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.
A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.
“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.
“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”
“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.
He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.
“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
Complex causes behind bottleneck
The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.
While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.
“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”
On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.
Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.
There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”
The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.
“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.
Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”
Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
Pharma companies trying to meet the demand
This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.
“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.
“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.
“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”
Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.
The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.
“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.
Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.
“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”
With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
Incredibly exciting potential
Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.
“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.
But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.
A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.
The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.
At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”
A version of this article first appeared on Medscape.com.
Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.
Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.
About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”
But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.
The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.
The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.
“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”
The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.
For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
Shortage affecting mostly myeloma patients
The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.
The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).
“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”
Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.
A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.
“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.
“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”
“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.
He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.
“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
Complex causes behind bottleneck
The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.
While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.
“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”
On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.
Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.
There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”
The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.
“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.
Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”
Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
Pharma companies trying to meet the demand
This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.
“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.
“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.
“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”
Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.
The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.
“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.
Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.
“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”
With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
Incredibly exciting potential
Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.
“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.
But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.
A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.
The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.
At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”
A version of this article first appeared on Medscape.com.
Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.
Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.
About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”
But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.
The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.
The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.
“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”
The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.
For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
Shortage affecting mostly myeloma patients
The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.
The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).
“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”
Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.
A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.
“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.
“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”
“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.
He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.
“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
Complex causes behind bottleneck
The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.
While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.
“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”
On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.
Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.
There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”
The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.
“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.
Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”
Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
Pharma companies trying to meet the demand
This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.
“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.
“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.
“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”
Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.
The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.
“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.
Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.
“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”
With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
Incredibly exciting potential
Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.
“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.
But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.
A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.
The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.
At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”
A version of this article first appeared on Medscape.com.